Cannabinoids and Cancer
The use of cannabinoids in treating the side effects
of cancer chemotherapy is more widely-studied than many
other potential therapeutic applications, and a number
of clinical studies have taken place investigating the
use of THC and synthetic cannabinoids as anti-emetic
agents. Two preparations have been licensed for
use in clinical treatment either in the UK or elsewhere,
including dronabinol (synthetic THC) and Nabilone (a
novel synthetic cannabinoid).
effects of chemotherapy and wasting diseases:
The powerful drugs used in cancer chemotherapy effectively
kill reproducing cells, including both the malignant
tumour cells and also, as a side effect, many cells
continually reproducing such as hair follicle cells
and those lining the gut, leading to severe nausea &
vomiting. These side effects can be very severe
and many patients find these difficult or impossible
to tolerate, falling into a wasting syndrome through
malnutrition brought on by a combination of reduced
appetite and poor gastrointestinal efficiency, which
can itself shorten life expectancy.
is variation between the effects of different anti-cancer
drugs. Cisplatin, one of the most effective chemotherapy
agents, induces vomiting in over 99% of patients not
taking an antiemetic, with around 10 vomiting episodes
per dose, although methotrexate causes emesis in under
10% of patients
are also variations in the efficacy and side effects
between conventional drugs used to treat nausea and
vomiting. The BMA  listed the side
effects of commonly-used anti-emetic drugs as follows:
Phenothiazines (prochlorperazine, haloperidol) - severe dystonic reactions,
drowsiness, dry mouth, blurred vision, urinary retention,
hypotension (low blood pressure), allergic reactions,
Metoclopramide - acute dystonic reactions, facial and muscle spasms,
drowsiness, restlessness, diarrhoea, depression
Domperidone - acute dystonic reactions
SSRAs (Ondansetron, gransisetron) - constipation,
headache, altered liver function. 
The main beneficial effects reported from use of cannabinoids
are a reduction in the incidence and severity of nausea
and vomiting (emesis), and stimulation of appetite,
together reducing the severity of cachexia - wasting
syndrome - in patients receiving chemotherapy treatment.
& Taylor  discovered "intrahypothalamic
anandamide initiates appetite by stimulation of CB1
receptors, thus providing evidence on the involvement
of hypothalamic endocannabinoids in appetite initiation."
Inui  concluded "cannabinoids...
act on the feeding-regulatory circuitry to increase
appetite and inhibit tumor-derived catabolic factors
to antagonize tissue wasting and/or host cytokine release.
Because weight loss shortens the survival time of cancer
patients and decreases performance status, effective
therapy would extend patient survival and improve quality
a 2003 review, Croxford
 noted "Dronabinol,
a commercially available form of delta(9)-THC, has been
used successfully for increasing appetite in patients
with HIV wasting disease", similarly,
Walsh et al
 noted "The
two proven indications for the use of the synthetic
cannabinoid (dronabinol) are chemotherapy-induced nausea
and vomiting and AIDS-related anorexia. Other possible
effects that may prove beneficial in the oncology population
include analgesia, antitumor effect, mood elevation,
muscle relaxation, and relief of insomnia."
Grotenhermen  agreed "Properties
of cannabis that might be of therapeutic use include
analgesia, muscle relaxation, immunosuppression, sedation,
improvement of mood, stimulation of appetite, antiemesis,
lowering of intraocular pressure, bronchodilation, neuroprotection
and induction of apoptosis in cancer cells."
Parker et al  concluded "endogenous
cannabinoids play a role in modulation of nausea".
Zurcher  recommended cannabinoids
for treatment of cancer-induced anorexia.
However Taskhin et al warned "The potential for marijuana smoking
to predispose to the development of respiratory malignancy
is suggested by several lines of evidence, including
the presence of potent carcinogens in marijuana smoke
and their resulting deposition in the lung, the occurrence
of premalignant changes in bronchial biopsies obtained
from smokers of marijuana in the absence of tobacco,
impairment of antitumor immune defenses by delta9-tetrahydrocannabinol,
and several clinical case series in which marijuana
smokers were disproportionately over represented among
young individuals who developed upper or lower respiratory
tract cancer. Additional well designed epidemiological
and immune monitoring studies are required to determine
the potential causal relationship between marijuana
use and the development of respiratory infection and/or
cancer." and Russmann et al  reported a case history of a patient suffering
a fatal stroke after smoking cannabis during a session
of cisplatin chemotherapy for testicular cancer. In
a general review, Drewe  noted "Chronic marijuana smoking is associated
with increased toxicity and the risk of cancer of the
respiratory tract. There is evidence of disturbance
of the immune system and teratogenic effects of chronic
cannabis use". Gardner et al
 found methanandamide "resulted
in an increased rate of tumor growth"
in mouse lung cells, but noted "methanandamide
augments tumor growth by a cannabinoid receptor-independent
Trials involving THC: Sallan et al (1975)
 found 10mg THC ∆significantly more
effective√ than placebo at reducing nausea and vomiting
in 22 chemotherapy patients. Chang et al  (1979) found 10mg oral or 17mg
smoked THC to decrease methotrexate-induced nausea and
vomiting compared to placebo in 14 of 15 patients.
Frytak et al
 found 15mg THC better than placebo
at inhibiting prochorperazine-induced emesis, but noted
some of the 116 gastrointestinal cancer patients to
find the side effects (sedation, ∆high√ dysphoria, hypotension
& tachycardia) intolerable. Orr & McKearnan
 found 7mg THC to be more effective
than prochlorperazine and placebo in 55 patients, of
which 82% reported a high. Lucas & Laszlo
 found 15mg or 2x5mg THC more
effective than placebo or standard regimes.
Chang et al  found 3-hourly
oral (10mg) or smoked (17.4mg) THC ineffective compared
with placebo in a small study of 8 patients receiving
adriamycin and cyclophosphamide. Niedhart et al  compared THC and Haloperidol
in 52 chemotherapy patients finding no difference in
efficacy between the two drugs. Gralla et al  found 10mg THC more effective
than placebo, but less effective than metoclopramide
in controlling cisplatin-induced vomiting in a 27-patient
study. Ungerleider et al
 in a large study of 214 patients,
found 4-hourly 7.5-12.5mg THC and 10mg prochlorperazine
equally effective in reducing nausea and vomiting, but
noted THC was preferred by more patients. Lane
 found significant improvement both
with THC (10mg dronabinol) and prochlorperazine, and
the combination more effective than either alone in
abolishing nausea and vomiting in 62 patients.
Trials involving Nabilone: Nagy et al
 studied 47 patients receiving cisplatin,
finding nabilone more effective than prochlorperazine
or placebo in reducing nausea & vomiting caused
by cisplatin. Herman et al
 found similar results with 113 patients
receiving cisplatin, cyclophosphamide & mustine
therapy. Einhorn et al
 studied 100 chemotherapy patients,
finding nabilone significantly more effective than prochlorperazine
and preferred by 75% of patients, but noted lethargy
and hypotension, similar results found in studies of
114 patients by Wada et al  , in 36 patients by Levitt et al  , 18 patients by Johannson et
al  , 26 patients by Ahmedzal et
al  and 24 patients by Niranan &
Mattison  .
et al  found ∆significant
reduction in nausea and vomiting with nabilone compared
to placebo√ in a study of 54 patients and noted acceptable
side effects to include dizziness (65%) and drowsiness
(51%). Niederle et al  found nabilone significantly
better than alizapride in reducing cisplatin-induced
nausea & vomiting in 20 patients. Pomeroy
 found nabilone superior to domperidone
in reducing vomiting episodes among 38 patients, as
did Dalzell et al  in a study of 23 children, finding
that despite more side effects it was preferred by two
thirds of respondents, and a study of 30 children by
Chan et al
 found nabilone superior to prochlorperazine.
involving natural cannabis: Vinciguerra et
 studied 56 cancer patients unresponsive
to conventional antiemetic agents, who were asked to
rate the effectiveness of marijuana compared to prior
chemotherapy cycles. Smoked marijuana was rated
as "moderately effective" or "highly
effective." by 78% of patients. The authors
concluded that marijuana had antiemetic efficacy, but
no control group was used and the patient population
varied with respect to prior marijuana use or THC therapy.
double-blind, cross-over, placebo-controlled study by
Levitt et al  compared smoked marijuana with oral THC among
20 patients receiving a variety of chemotherapy drugs.
The efficacy was similar, with 25% of patients achieving
complete control over vomiting. Seven patients (35%)
indicated apreference for oral THC over marijuana; 4
patients (20%) preferred smoked marijuana and 9 patients
(45%) expressed no preference.
study investigated the time course of antiemetic control,
advantages of self-titration with the smoked marijuana,
or ability of patients to swallow the pills. Patients
with severe vomiting are unlikely to be able to swallow
or keep pills down long enough for them to take effect.
The onset of drug effect is much faster with smoked
THC in cannabis than it is for oral delivery
 , and the differences in cannabinoid
content of smoked cannabis compared to the oral THC
route can alter the users perceptions and subjective
effects. Haney et al
 reported smoked cannabis to make users
feel ∆mellow√ whereas oral THC did not. . Although
many cannabis users claim that smoking the drug provides
more effective relief from vomiting than oral THC, no
controlled studies have yet been published which firmly
establish this to be the case.
of Major Recent Inquiries: The British Medical
are undoubtedly effective as anti-emetic agents in vomiting
induced by anti-cancer drugs" and
that "Systematic trials of the effectiveness
of cannabinoids in combatting vomiting resulting from
different chemotherapy agents should be carried out".
United States Institute of Medicine report
patients already experiencing severe nausea or vomiting,
pills are generally ineffective, because of the difficulty
in swallowing or keeping a pill down, and slow o nset
of the drug effect. Thus an inhalation (but, preferably
not smoking) cannabinoid drug delivery system would
be advantageous for treating chemotherapy-induced nausea."
is possible that the harmful effects of smoking marijuana
for a limited period of time might be outweighed by
the antiemetic benefits of marijuana, at least for,
patients for whom standard antiemetic therapy is ineffective
and who suffer from debilitating emesis. Such patients
should be evaluated on a case by case basis"
House of Lords Science & Technology Select Committee
made the following findings and recommendations  :
and cannabinoids are likely to be of benefit as anti-emetics
only to the small proportion of patients who do not
respond to existing treatments, or possibly in the treatment
of the delayed stages of emesis which can occur for
some days following cancer chemotherapy, and which do
not respond well to the serotonin antagonists. Nevertheless,
cannabinoids are undoubtedly effective as anti≠emetics
and more research in this field might explore their
use in combination with the serotonin antagonists, help
to determine for which patients they are most appropriate,
and examine the potential of the allegedly less psychoactive
cannabinoid D8≠THC, for which there have been encouraging
preliminary clinical results"
cannabis itself, the cannabinoid THC (dronabinol) and
its analogue nabilone are already accepted by the Government
as having medical value -- producing the anomaly that,
while cannabis itself is banned as a psychoactive drug,
THC, the principal substance which makes it psychoactive,
is in legitimate medical use. Some of our witnesses
are prepared to contemplate wider medical use of the
cannabinoids, but not of cannabis itself. We disagree,
since some users of both find cannabis itself more effective.
We do, however, welcome the inclusion of THC in the
trials proposed by the Asscher group, in like-for-like
comparison with cannabis itself"
"Dronabinol (THC), though not
licensed in this country, has already been moved to
Schedule 2 to the Misuse of Drugs Regulations, and nabilone
is a licensed medicine and not a controlled drug; so
no Government action is required in either case to permit
clinical trials or indeed prescription. ...we recommend
that the Government should raise the matter of rescheduling
the remaining cannabinoids with the WHO in due course,
in order to facilitate research."
principal reason for recommending that the law be changed,
to make legal the use of cannabis for medical purposes,
is compassionate. Illegal medical use of cannabis is
quite widespread; it is sometimes connived at and even
in some cases encouraged by health professionals; and
yet at present it exposes patients and in some cases
their carers to all the distress of criminal proceedings,
with the possibility of serious penalties. We acknowledge
that, if our recommendation were implemented, the United
Kingdom would be moving out of step with many other
countries; we consider that the Government should not
be afraid to give a lead in this matter in a responsible
scientific developments-anti-tumour activity:
Recent scientific advances in the study of cannabinoid
receptors and endocannabinoids have produced exciting
new leads in the search for anti-cancer treatments,
with CB1 and CB2 agonists (like THC) associated with
tumour regression, reduced proliferation and blood supply
to tumours, and apoptosis (programmed cell-suicide)
among cells of various cancer types.
et al  reported "Cannabinoids,
the active components of marijuana and their derivatives,
induce tumor regression in rodents... Inhibition of
tumor angiogenesis may allow new strategies for the
design of cannabinoid-based antitumoral therapies."
Sanchez et al  reported "growth
of the rat glioma (one of the most malignant forms of
cancer) is inhibited by psychoactive cannabinoids"
and that "local
administration of (a) selective CB(2) agonist... induced
a considerable regression of malignant tumors".
a study of skin cancers, Casanova et al
 found "In
cell culture experiments pharmacological activation
of cannabinoid receptors induced the apoptotic death
of tumorigenic epidermal cells, whereas the viability
of nontransformed epidermal cells remained unaffected.
Local administration of the mixed CB(1)/CB(2) agonist
WIN-55,212-2 or the selective CB(2) agonist JWH-133
induced a considerable growth inhibition of malignant
tumors generated by inoculation of epidermal tumor cells
into nude mice. Cannabinoid-treated tumors showed an
increased number of apoptotic cells. This was accompanied
by impairment of tumor vascularization, as determined
by altered blood vessel morphology and decreased expression
of proangiogenic factors" Furthermore
Di Marzo et al  noted the "anti-proliferative
effect of anandamide in human breast cancer cells"
was enhanced by Palmitoylethanolamide. De Petrocellis
 considered this effect to be mediated
by CB1 and vanilloid receptors. Fowler et al
 concluded "the
antiproliferative effects of anandamide were not solely
mediated by either its hydrolysis to produce arachidonic
acid or its CB receptor-mediated activation of phospholipase
A(2) since palmitoyltrifluoromethyl ketone did not prevent
the response to anandamide."
a study of thyroid cancer cells, Portella et al
 noted "Stimulation
of cannabinoid CB1 receptors ... inhibits the growth
of a rat thyroid cancer cell-derived tumor in athymic
and concluded "CB1
receptor agonists might be used therapeutically to retard
tumor growth in vivo by inhibiting at once tumor growth,
angiogenesis, and metastasis"
Mimeault et al  , studying prostate cancer, reported
potent anti-proliferative and cytotoxic effects of (anandamide)
on metastatic prostatic cancer cells might provide basis
for the design of new therapeutic agents for effective
treatment of recurrent and invasive prostatic cancers."
Recht et al
 found a metabolite of THC ajulemic
acid (AJA; dimethylheptyl-THC-11-oic acid) to be "a
potent anti-inflammatory agent without psychoactive
properties... Its very favorable toxicity profile, including
lack of psychoactivity, makes it suitable for chronic
the effect of cannabinoid receptor agonists and antagonists
on different types of colorectal cancer cells, Ligresti
 found "Anandamide,
2-AG, and the CBR agonist HU-210 potently inhibit CaCo-2
cell proliferation. This effect is blocked by the CB(1)
antagonist SR141716A, but not by the CB(2) antagonist
SR144528, and is mimicked by CB(1)-selective, but not
CB(2)-selective, agonists. In DLD-1 cells, both CB(1)
and CB(2) receptors mediate inhibition of proliferation."
Jacobsson et al
 concluded "the
antiproliferative effects of the endocannabinoids upon
(rat glioma) cells are brought about by a mechanism
involving combined activation of both vanilloid receptors
and to a lesser extent cannabinoid receptors"
Gomez del Pulgar  et al found THC to cause death of glioma cells
due to local synthesis of ceramide, and demonstrated  a neuroprotective effect of cannabinoids on astrocytes.
et al  found reduced
CB1-receptor activity to be associated with development
of pituitary cancers, noting "estrogen-induced
pituitary hyperplastia was associated with a marked
reduction in CB1 receptors" Pagotto
 found elevated CB1 receptor activity
and endocannabinoids in tumorous pituitary gland cells,
results of this study point to a direct role of cannabinoids
in the regulation of human pituitary hormone secretion."
Rubovitch et al
 demonstrated CB1-receptor-agonist modulated
stimulation of calcium ion uptake in neuroblastoma cells.
Bifulco et al  found an analogue
of anandamide to inhibit oncogene-mediated tumour growth
via CB1-receptor activity.
a 2002 review. Guzman et al
 concluded "cannabinoid
administration induces regression of malignant gliomas
in rodents by a mechanism that may involve sustained
ceramide generation and extracellular signal-regulated
kinase activation. In contrast, most of the experimental
evidence indicates that cannabinoids may protect normal
neurons from toxic insults, such as glutamatergic overstimulation,
ischaemia, and oxidative damage. Regarding immune cells,
low doses of cannabinoids may enhance proliferation,
whereas high doses of cannabinoids usually induce growth
arrest or apoptosis." In 2003
 added "Cannabinoids
- the active components of Cannabis sativa and their
derivatives - exert palliative effects in cancer patients
by preventing nausea, vomiting and pain and by stimulating
appetite. In addition, these compounds have been shown
to inhibit the growth of tumour cells in culture and
animal models by modulating key cell-signalling pathways.
Cannabinoids are usually well tolerated, and do not
produce the generalized toxic effects of conventional
et al  concluded "Modulation
of the endocannabinoid system interferes with cancer
cell proliferation either by inhibiting mitogenic autocrine/paracrine
loops or by directly inducing apoptosis; however, the
proapoptotic effect of anandamide is not shared by other
endocannabinoids and suggests the involvement of non-cannabinoid
receptors" Bifulco & Di Marzo  reviewed studies
of antitumour activity and concluded "Recently, evidence has accumulated
indicating that stimulation of cannabinoid receptors
by either THC or the endocannabinoids influence the
intracellular events controlling the proliferation and
apoptosis of numerous types of cancer cells, thereby
leading to anti-tumour effects both in vitro and in
vivo. This evidence is reviewed here and suggests that
future anti-cancer therapy might be developed from our
knowledge of how the endocannabinoid system controls
the growth and metastasis of malignant cells."
& Lymphomas: There are few scientific
references specifically to research in Hodgkins disease.
Abrahamov et al  reported the effects of a study
of delta-8-THC in children suffering from haematological
cancers and undergoing chemotherapy, noting "Vomiting was completely prevented.
The side effects observed were negligible.".
However Lockwood  reported a case history of "Marihuana
and alcohol intolerance"
in a Hodgkin's disease patient.
a study of lymphobastomas, McKallip et al
 found "human tumor cells were
also susceptible to apoptosis induced by THC, HU-210,
anandamide, and the CB2-selective agonist JWH-015. This
effect was mediated at least in part through the CB2
receptors because pretreatment with the CB2 antagonist
SR144528 partially reversed the THC-induced apoptosis.
Also, because CB2 agonists lack psychotropic effects,
they may serve as novel anticancer agents to selectively
target and kill tumors of immune origin." Islam
et al  noted a "high
expression of the cannabinoid receptor 1 (CB1) gene
in all Mantle Cell Lymphoma cases analysed"
Joosten et al  postulated that
an overabundance of CB2 receptors in transgenic mice
may increase predisposition to leukaemia, and Jorda
 concluded "a
major function of Cb2 receptor expressed on myeloid
leukemia cells or normal splenocytes is stimulation
-side effects of chemotherapy: Levitt  in an early review
presentation, suggested:"The use of cannabinoids as cancer
chemotherapy anti-emetics represents, in essence, the
use of a drug with a relatively undefined mechanism
of action to treat the side effects of other drugs,
also with relatively undefined mechanisms of action,
which are being used to treat cancer, a disease or series
of diseases the precise nature of which remains enigmatic."
Since Levitt√s review, there have been major advances
in cannabinoid pharmacology and in understanding of
the cancer disease process. In particular, research
by Herkenham et al
 demonstrated the presence of numerous
cannabinoid receptors in the nucleus of the solitary
tract, a brain center that is important in the control
other recently developed anti-emetics are as effective
or more effective than oral THC, nabilone or smoked
cannabis, for certain individuals unresponsive to conventional
anti-emetic drugs, the use of smoked cannabis can provide
relief more effectively than oral preparations which
may be difficult to swallow or be expelled in vomit
before having a chance to take effect. The psychoactive/euphoriant
effects of THC or smoked cannabis may provide an improvement
in mood, whereas several conventional preparations e.g.
phenothiazines such as haloperidol (known as ∆major
tranquillisers√ and also used in the treatment of psychoses
such as schizophrenia), may produce unwanted side effects
such as excessive sedation, flattening of mood, and/or
distressing physical ∆extrapyramidal√ symptoms such
as uncontrolled or compulsive movements. A 1991 US survey  found public support for marijuana
use by cancer patients.
In the USA, synthetic THC (Dronabinol) is available
for use as an adjunct to cancer chemotherapy treatment,
and in the UK, both the British Medical Association
and House of Lords recognised the potential for use
of cannabinoids in preventing nausea and vomiting.
-Direct anti-cancer activity of cannabinoids.
Some researchers have investigated the link between
mental and spiritual state and cancer remission, associating
the cannabinoid system with the expression of pleasure
on the one hand and stress on the other. Lissoni
et al  reviewed the effect of psychospiritual
state on cancer growth or suppression, noting "Stress,
anxiety and depressive states are associated with immunosuppression
and enhanced frequency of tumors. On the other hand,
the states of sexual pleasure and spiritual joy enhance
the immune efficacy, by counteracting tumor onset and
dissemination. The biochemistry of pleasure and immunostimulation
is mainly mediated by pineal indoles and cannabinergic
substances, whereas that of stress, anxiety and depression
is associated with enhanced production of adrenal steroids,
opioids and catecholamines."
would appear to be growing evidence of direct anti-tumour
activity of cannabinoids, specifically CB1 and CB2 agonists,
in a range of cancer types including brain (gliomas),
skin, pituitary, prostate and bowel. The antitumour
activity has led in laboratory animals and in-vitro
human tissues to regression of tumours, reductions in
vascularisation (blood supply) and metastases (secondary
tumours), as well as direct inducement of death (apoptosis)
among cancer cells. Indeed, the complex interactions
of endogenous cannabinoids and receptors is leading
to greater scientific understanding of the mechanisms
by which cancers develop.
smoking of cannabis releases a number of non-cannabinoid
carcinogens into the lungs and upper respiratory tract,
and a number of researchers (notably Tashkin and colleagues)
have identified pre-cancerous changes in lung cells.
The failure of these researchers to discover significant
evidence of actual cancer cells in the lung may be attributed
to these anti-cancer activities of cannabinoids including
THC counteracting the effects of other carcinogens in
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